Radical-free biology of oxidative stress

Abstract

Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

“…A redox dysregulation can affect cell proliferation/differentiation, energy metabolism and neurotransmission via an alteration of redox-sensitive protein function. 10 Converging data indicate a role for redox dysregulation in the pathophysiology of schizophrenia. [11][12][13][14] In some studies, decreased glutathione (GSH) levels, the main cellular non-protein antioxidant and redox regulator, 10,15 have been reported in the cerebrospinal fluid and prefrontal cortex of patients by using magnetic resonance spectroscopy (MRS) 16,17 and in post-mortem tissues.…”

“…10 Converging data indicate a role for redox dysregulation in the pathophysiology of schizophrenia. [11][12][13][14] In some studies, decreased glutathione (GSH) levels, the main cellular non-protein antioxidant and redox regulator, 10,15 have been reported in the cerebrospinal fluid and prefrontal cortex of patients by using magnetic resonance spectroscopy (MRS) 16,17 and in post-mortem tissues. 14,18 We thus proposed that a redox dysregulation represents one hub on which converge various causal genetic and environmental risk factors during neurodevelopment, leading to structural and functional connectivity impairments.…”

Antioxidant effect of phycocyanin on oxidative stress induced with monosodium glutamate in rats

“…However, this substance is neurotoxic and the excess of monosodium glutamate in the brain allows high affluence of calcium inside the neuronal cell, providing the formation of free radicals (FR) with cell death (Natali, 2001;Cesaretti, 2006). The oxidative stress damage is minimized by the antioxidant defense system and can be classified as natural or synthetic (Jones, 2008;Halliwel, 2007). Nowadays, there is a growing interest in the natural antioxidants due to their low toxicity.…”

Oxidative stress in carotid arteries of patients submitted to carotid endarterectomy. The role of aging process

“…It has been accepted that ROS are involved in the development of atherosclerosis 25 10,30 . By converting hydrogen peroxide into water, CAT constitutes a primary antioxidant defense system and could protect cells from ROS and its deleterious consequences 31 .…”